Journal of pharmaceutical sciences最新文献

{"title":"Structure, Morphology and Surface Properties of α-Lactose Monohydrate in Relation to its Powder Properties.","authors":"Thai T H Nguyen, Cai Y Ma, Ioanna D Styliari, Parmesh Gajjar, Robert B Hammond, Philip J Withers, Darragh Murnane, Kevin J Roberts","doi":"10.1016/j.xphs.2024.10.031","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.031","url":null,"abstract":"<p><p>The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction contrast tomography. Interestingly, from aqueous solution fastest growth is found to lie along the b-axis, i.e. the longest unit cell dimension of the αLMH crystal structure reflecting the greater opportunities for solvation on the prism compared to the capping faces leading to their slower relative growth rates. The tomahawk morphology reflects the presence of β-lactose which asymmetrically binds to the capping surfaces creating a polar morphology. The crystal lattice energy is dominated by van der Waals interactions (between lactose molecules) with electrostatic interactions contributing the remainder. Predicted total surface energies are in good agreement with those measured at high surface coverage by inverse gas chromatography, albeit their dispersive contributions are found to be higher than those measured. The calculated surface energies of crystal habit surfaces are not found to be significantly different between different crystal surfaces, consistent with αLMH's known homogeneous binding to drug molecules when formulated. Surface energies for different morphologies reveals crystals with the elongated crystal morphologies have lower surface energies compared to those with a triangular or tomahawk morphologies, correlating well with literature data that the surface energies of the lactose carriers are inversely proportional to their aerosol dispersion performance.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cocrystal screening in minutes by solution-mediated phase transformation (SMPT): Preparation and characterization of ketoconazole cocrystals with nine aliphatic dicarboxylic acids.","authors":"Junguang Yu, Rodger F Henry, Geoff G Z Zhang","doi":"10.1016/j.xphs.2024.10.046","DOIUrl":"10.1016/j.xphs.2024.10.046","url":null,"abstract":"<p><p>The rapid and efficient cocrystal screening, based on solution-mediated phase transformation (SMPT), was applied to the screening of cocrystals between ketoconazole (KTZ) and nine aliphatic dicarboxylic acids. Cocrystals formed successfully, in minutes, with a change of suspension characteristics, either a cake formation or the formation of large particles. Bulk cocrystals were characterized by powder X-ray diffraction, thermal analysis, and Raman spectroscopy. Single crystals were grown, and molecular structures were determined. Three previously reported cocrystals were reproduced, and six new cocrystals were discovered, including one that was reported as a failure in literature by solution or grinding method. Two hydrogen-bonded motifs are observed in these nine cocrystals: Most cocrystals form hydrogen bonded discrete tetramer with two KTZ and two acids molecules; while two cocrystals form infinite chain. This study demonstrated the high efficacy of cocrystal generation using the slurry screening method. It should be fully utilized in future cocrystal screening.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental validation of a parenteral permitted daily exposure value for cleaning-induced degradants from recombinant therapeutic proteins with in vitro immunogenicity assays.","authors":"Joseph R Cohen, Marisa K Joubert, Syeda Tabassum, Allyson Capili, Julia Carreon, Cathie Xiang, Siddharth Prabhu, Anthony Merlo, Dan Mytych, David G Dolan, Ram Kouda","doi":"10.1016/j.xphs.2024.10.041","DOIUrl":"10.1016/j.xphs.2024.10.041","url":null,"abstract":"<p><p>Multiproduct manufacturing of biotherapeutic proteins generate cleaning-induced protein degradants because of extreme pH and temperature conditions during the cleaning process. Cleaning Acceptance limits are calculated based on the maximum allowable carryover (MAC) assessment of the previously manufactured active pharmaceutical ingredient (API) - or drug product - based on the permitted daily exposure (PDE) of the previously manufactured API into the dose of subsequent product. In this study, we tested a previously determined PDE value for cleaning-induced protein degradants of 650 µg/dose. A bench-scale cleaning method was used to generate cleaning induced degradants from both a half-life extension (HLE) BiTE® molecule and a mAb product. For this investigation, degradants of HLE BiTE®-A and mAb-1 were characterized alone or after spiking of 650 µg of degradants of HLE BiTE®-A or 650 µg degradants of mAb-1, into mAb-1, respectively. These samples were characterized by endotoxin testing, size exclusion chromatography (SEC), light obscuration by HIAC, and micro-fluidic imaging (MFI). These results suggest that significant degradation of the molecule occurs because of the cleaning procedure, and it is no longer in the intact form or active state. The potential immogenic impact was assessed using a cell line assay to assess immune activation, and a human Peripheral Blood Mononuclear Cell (PBMC) assay to assess T cell activation, T cell proliferation, and cytokine release after 20 h and 7 days. Findings from the various in vitro cell-based immune activation assays suggest that the presence of 650 µg of carryover of degradants either alone or spiked into the same or a cross-product do not increase immunogenicity risk in cell-based assays - suggesting that the current PDE of 650 µg/dose for cleaning-induced degradant carryover does not have a risk of immunogenicity in patients.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitation of AAV in a dual-vector system using SV-AUC.","authors":"Alexander E Yarawsky, Carlo Ciatto, Peter Slade, Natalya I Figueroa, John W Burgner, Michael T DeLion, Lake N Paul","doi":"10.1016/j.xphs.2024.10.049","DOIUrl":"10.1016/j.xphs.2024.10.049","url":null,"abstract":"<p><p>Sedimentation velocity analytical ultracentrifugation (SV-AUC) has become the \"gold standard\" for characterization of the empty, partial, and full capsids of gene therapy products (e.g., AAV and Adenovirus vectors). Other techniques, such as SEC-MALS, TEM, and mass photometry, are commonly used for capsid quantitation, however, the resolving power of these techniques is lacking. In this body of work, SV-AUC was implemented in the characterization of a dual-vector AAV system where the difference in packaged genomes was ∼400 nucleotides. The instrument parameters and SV-AUC analysis were optimized to accurately quantitate both AAV vectors with less than 8% error and with highly correlated linearity (R² > 0.99) as compared to ddPCR. The results of this work highlight the resolution and accuracy of dual-vector capsid quantitation by SV-AUC and demonstrate the use of the powerful Bayesian analysis implemented in the SEDFIT analysis software.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of crystal disorder on the solid-state stability of Olanzapine.","authors":"Jayant Iyer, Matilde Barbosa, João F Pinto, Amrit Paudel","doi":"10.1016/j.xphs.2024.10.047","DOIUrl":"https://doi.org/10.1016/j.xphs.2024.10.047","url":null,"abstract":"<p><p>Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation propensities of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the correlation between nuclear localization levels and genome editing efficiencies of Cas12a fused with nuclear localization signals.","authors":"Tomohito Tsukamoto, Haruna Mizuta, Eiko Sakai, Fuminori Sakurai, Hiroyuki Mizuguchi","doi":"10.1016/j.xphs.2024.10.029","DOIUrl":"10.1016/j.xphs.2024.10.029","url":null,"abstract":"<p><p>Genome editing technology using the CRISPR-Cas system is attracting much attention not only as a promising experimental tool for analysis of genome functions, but also as a novel therapeutic approach for genetic disorders. Among the various types of Cas proteins, Cas12a is expected to be a promising gene editing tool due to its unique properties, including low off-target effects. As Cas proteins are of prokaryotic origin, they need to be fused with appropriate localization signals to perform their function in eukaryotic cells. Cas12a proteins fused with a nuclear localization signal (NLS) have been developed so far, but the relation between the nuclear localization activity and the genome editing efficiency has not been fully elucidated. Here, utilizing two Cas12a orthologs, AsCas12a and LbCas12a, with various number of NLSs derived from various origins, we revealed that the improved nuclear localization resulted in increased genome editing efficiencies when expressed using adenovirus (Ad) vector in cultured cells. However, when they were expressed in mouse liver, the improvement of the nuclear localization activity was not necessarily required to achieve the maximum genome editing efficiency four weeks after Ad vector administration. These data indicated that the optimized NLS modification of Cas12a proteins in vitro situations differed from that in vivo.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of macrocyclic peptide drug interactions with bile salts and biorelevant colloids via single amino acid mutations and ¹H nuclear magnetic resonance (NMR) spectroscopy.","authors":"Tahnee J Dening, José G Napolitano, Jessica L Ochoa, Justin T Douglas, Michael J Hageman","doi":"10.1016/j.xphs.2024.10.021","DOIUrl":"10.1016/j.xphs.2024.10.021","url":null,"abstract":"<p><p>There is growing interest in the oral delivery of poorly permeable peptide drugs; however, the effect of biorelevant colloids found in the aqueous gastrointestinal environment on peptide drug solution behavior has been largely understudied. In this work, we detail the molecular level interactions between octreotide, a water-soluble macrocyclic peptide drug, and biorelevant colloids, i.e. bile salt micelles and bile salt-phospholipid mixed micelles, via dialysis membrane flux experiments and proton nuclear magnetic resonance (¹H NMR) spectroscopy. A modified alanine scan was employed to generate eight mutated octreotide analogs; the impact of individual amino acid mutations on peptide dialysis membrane flux rates in micellar (trihydroxy and dihydroxy) bile salt solutions as well as fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) was evaluated and compared against the parent peptide, octreotide. We show that octreotide interacts more strongly with dihydroxy bile salt micelles than trihydroxy bile salt micelles in solution, and in FaSSIF/FeSSIF media, octreotide mainly interacts with the phospholipid component. These interactions are largely mediated by hydrophobic interactions of octreotide's aromatic residues as well as electrostatic interactions between octreotide's basic Lys residue and terminal amine.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissolution mechanisms of amorphous solid dispersions: Role of polymer molecular weight and identification of a new failure mode.","authors":"Alexandru Deac, Chailu Que, Michelle L Cousineau, Anura S Indulkar, Yi Gao, Geoff G Z Zhang, Lynne S Taylor","doi":"10.1016/j.xphs.2024.10.026","DOIUrl":"10.1016/j.xphs.2024.10.026","url":null,"abstract":"<p><p>The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of poly (vinylpyrrolidone) (PVP) were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biowaiver monographs for immediate-release solid oral dosage forms: Lemborexant.","authors":"Kristian Beran, Bertil Abrahamsson, Naseem Charoo, Rodrigo Cristofoletti, René Holm, Atsushi Kambayashi, Peter Langguth, Mehul Mehta, Alan Parr, James E Polli, Vinod P Shah, Jennifer Dressman","doi":"10.1016/j.xphs.2024.10.030","DOIUrl":"10.1016/j.xphs.2024.10.030","url":null,"abstract":"<p><p>Lemborexant is a dual orexin receptor antagonist assigned to class II of the Biopharmaceutics Classification System (BCS). Thus, the ICH M9 Guideline excludes immediate-release (IR) solid oral dosage forms containing lemborexant from BCS-based biowaivers, irrespective of their in vitro dissolution behavior. By contrast, classification of lemborexant according to the refined Developability Classification System (rDCS) falls into class I, indicating few biopharmaceutics risks. Customized rDCS investigations identify dissolution as the main risk factor, in line with clinical data in humans which suggest that the absorption of lemborexant is limited neither by solubility nor by permeability. Instead, any risks lie in dissolution. Analysis by the rDCS coupled with biorelevant dissolution testing thus provides a way forward for manufacturers to mitigate the risks associated with changes in formulation or introduction of a generic version prior to running clinical bioequivalence (BE) studies. As a way forward regarding biowaivers for lemborexant and similar cases, where justifying BE based on the current BCS-based approach is not possible, a four-step pathway towards establishing BE virtually could be adopted as follows: (i) rDCS analysis to identify critical bioavailability attributes, (ii) comparative (biorelevant) dissolution testing, (iii) Physiologically Based Biopharmaceutics Modeling (PBBM), and (iv) virtual BE assessment.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of dissolution medium pH and ionization state of the drug on the release performance of amorphous solid dispersions.","authors":"Anura S Indulkar, Samantha Alex, Geoff G Z Zhang","doi":"10.1016/j.xphs.2024.10.028","DOIUrl":"10.1016/j.xphs.2024.10.028","url":null,"abstract":"<p><p>Amorphous solid dispersions (ASDs) are widely employed as a strategy to improve oral bioavailability of poorly water soluble compounds. Typically, optimal dissolution performance from a polyvinylpyrrolidone vinyl acetate (PVPVA) based ASD is observed at relatively low drug loading limit. Above a certain drug load, termed limit of congruency (LoC), the release from ASDs significantly decreases. So far, the majority of the dissolution behavior has been tested in conditions where the drug primarily exists in unionized form. In this work, the impact of pH of the dissolution environment on the release performance of ASDs of an ionizable drug was studied. Atazanavir (ATZ), a weakly basic drug with a pK_a of 4.5 was used as a model compound and PVPVA was used as a non-ionizable matrix polymer. Dissolution rate was measured using Wood's apparatus which normalizes the surface area of the dissolving tablet. The pH of the dissolution media was varied between 1 and 6.8, to cover a range where ATZ exists as >99 % ionized or unionized species. At pH 6.8, near complete release was observed only when the drug load was ≤ 6 %. Unlike typically observed drastic decline in release behavior for PVPVA based ASDs above LoC, ATZ ASDs underwent gradual decline in dissolution behavior when the DL was increased to 8 %. This was attributed to potential formation of an ATZ-PVPVA associated phase with dissolution rate slower than neat PVPVA. However, the 10 % DL ASD showed negligible ATZ release. On another extreme (pH 1) where ATZ is ∼100 % ionized, the dissolution rate of ATZ was faster than that of PVPVA. ASD dissolution rate was found to be slower than that of the neat drug but faster than PVPVA and interestingly, did not change with DL. This can be attributed to formation of an ionized ATZ-PVPVA phase which controls the dissolution rate of the ASD. At pH 3, where the drug is ∼97 % ionized, near complete release was observed for drug loads ≤ 8 %. To observe significant increase in drug loading with near complete release, >98 % ionization of ATZ was required. At pH 2 where ATZ is ∼99.7 % ionized, near complete release was observed for drug loads up to 30 %. Furthermore, the deterioration in dissolution performance with an increase in drug load continued to be gradual at pH 2. The enhancement in dissolution performance did not correlate with solubility enhancement of ATZ due to ionization. We theorize that the enhancement in the dissolution performance due to ionization is the result of formation of an ionized ATZ-PVPVA phase which increases the hydrophilicity and the miscibility of the ASD. This can help resist water induced phase separation during ASD dissolution and therefore, result in continuous, and congruent dissolution of the drug and polymer.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}